Enhancing T Cell Receptor Stability in Rejuvenated iPSC-Derived T Cells Improves Their Use in Cancer Immunotherapy
Enhancing T Cell Receptor Stability in Rejuvenated iPSC-Derived T Cells Improves Their Use in Cancer Immunotherapy
复制标题
DOI：
10.1016/j.stem.2018.10.005
复制
发表时间：
2018-12-06
期刊：
影响因子：
23.9
通讯作者：
Kaneko, Shin
中科院分区：
文献类型：
--
作者：
Minagawa, Atsutaka;Yoshikawa, Toshiaki;Kaneko, Shin
有限的T细胞可用性和增殖性耗竭是成功的基于T细胞的免疫疗法的主要障碍，并且可以通过使用来源于抗原特异性T细胞（T-iPSC）的“再生的”诱导多能干细胞来克服。然而，严格的抗原特异性对于安全和有效的T细胞免疫治疗是必不可少的。在这里，我们报告了来自人T-iPSC的CD 8 α 8 T细胞在体外分化的CD 4/CD 8双阳性阶段期间通过T细胞受体（TCR）α链基因的额外重排而失去其抗原特异性。T-iPSC中重组酶基因的CRISPR敲除阻止了这种额外的TCR重排。此外，当CD 8 α 8 T细胞从用抗原特异性TCR转导的单核细胞来源的iPSC分化时，它们显示转导的TCR的单克隆表达。TCR稳定的再生CD 8 α 8 T细胞有效抑制异种移植癌症模型中的肿瘤生长。这些方法可能有助于安全有效的再生T细胞免疫疗法。
Limited T cell availability and proliferative exhaustion present major barriers to successful T cell-based immunotherapies and may potentially be overcome through the use of "rejuvenated" induced pluripotent stem cells derived from antigen-specific T cells (T-iPSCs). However, strict antigen specificity is essential for safe and efficient T cell immunotherapy. Here, we report that CD8 alpha 8 T cells from human T-iPSCs lose their antigen specificity through additional rearrangement of the T cell receptor (TCR) alpha chain gene during the CD4/CD8 double positive stage of in vitro differentiation. CRISPR knockout of a recombinase gene in the T-iPSCs prevented this additional TCR rearrangement. Moreover, when CD8 alpha 8 T cells were differentiated from monocyte-derived iPSCs that were transduced with an antigen-specific TCR, they showed monoclonal expression of the transduced TCR. TCR-stabilized, regenerated CD8 alpha 8 T cells effectively inhibit tumor growth in xenograft cancer models. These approaches could contribute to safe and effective regenerative T cell immunotherapies.